Dendrimers (Greek: dendri: “tree-like” and meros: “part of”) are monodisperse macromolecules with well-defined branched architecture and symmetrical morphology (Bosman, A. W., Chemical Reviews 99, 1665-1688, (1999)). Dendrimers are comprised of a series of branches extending outward from an inner core. These branches are arranged in layers, called generations, and represent the repeating units (monomer) of a dendrimer. A typical dendrimer molecule contains an inner core, layers of repeating units, and multiple terminal functional groups. The active moieties are either encapsulated into the core/cavities or grafted onto the surface of dendrimers. The dendrimers are distinct from other nanocarriers in that they possess a tunable structure, empty intramolecular cavity, and multifunctional surface (Duncan, R., Advanced Drug Delivery Reviews 57, 2215-2237, (2005)). The existence of interior void spaces inside the dendrimer, particularly the high generation dendrimers, becomes appropriate locations for drug or gene material loading and transportation. Generally, payloads are held inside the dendrimer Cavities via covalent attachment, hydrophobic interaction, hydrogen bonds, or charge interaction. The degradable or cleavable bonds like ester, imine, acetal and ketal are more preferred in covalent bonding since they function as the triggers of environmental response release.
The first dendrimer-like structure was reported by Vögtle and coworkers in 1978 (Egon Buhleier, W. W., Synthesis, 155-158, (1978)), who synthesized polypropylenimine (PPI). The term “dendrimer” was suggested by Tomalia et al. in 1985 who along with Newkome et al. (Newkome, G. R., Journal Of Organic Chemistry 50, 2003-2004 (1985)) synthesized dendrimers of higher generation with well-defined structures (Tomalia, D. A., Polymer Journal 17, 117-132, (1985)). The dendrimers are prepared using either divergent (Newkome, G. R., Journal Of Organic Chemistry 50, 2003-2004 (1985)) or convergent (Hawker, C. J., Journal Of The American Chemical Society 112, 7638-7647, (1990)) strategies. In a divergent approach, pioneered by Vogtle (Egon Buhleier, W. W., Synthesis, 155-158, (1978)), Donald A. Tomalia, and Newkome (Newkome, G. R., Journal Of Organic Chemistry 50, 2003-2004 (1985)), dendrimer synthesis proceeds outwards from multifunctional core to surface, whereas in a convergent approach, pioneered by Frechet and coworkers (Hawker, C. J., Journal Of the American Chemical Society 112, 7638-7647, (1990)), dendrimer synthesis proceeds inward, from surface to core. Some of the most common dendrimers are polyamidoamine (PAMAM); poly(L-lysine) (PLL); polyamide; polyester (PGLSA-OH); polypropylenimine (PEI); and poly(2,2-bis(hydroxymethyl)propionic acid (bis-MPA).
Although dendrimers have found wide application in drug and gene delivery, and diagnostics, their use is restricted due to reticuloendothelial system (RES) uptake, immunogenicity, hemolytic toxicity, cytotoxicity, hydrophobicity.
Statistics on dendrimer PEGylation shows that most of the studies have focused on dendrimer surface modification. The toxicity from dendrimer branch/core structure is still a potential threat for safe use of dendrimers. In addition, since the sizes of currently developed dendrimers are less than 100 nanometers, these are prone to excretion by kidney.